AACE: Novel Agent Promising for Rare Metabolic Disorder

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Explain that among patients with the rare disorder lipodystrophy, metreleptin given once or twice daily resulted in large decreases from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and triglycerides.

Note that seventeen of the 55 patients had a treatment-emergent adverse event judged to be related to metreleptin, including fatigue, hypoglycemia, alopecia, and weight loss.

SAN DIEGO -- An investigational recombinant analogue of the hormone leptin may solve some problems for patients with lipodystrophy, results from an uncontrolled trial showed.

Among 55 patients with the rare disorder, metreleptin given once or twice daily resulted in large drops from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose, and triglycerides, according to Christian Weyer, MD, senior vice president of research and development for Amylin Pharmaceuticals, which is developing the agent.

Of the 41 patients who started the trial with diabetes, hypertriglyceridemia, or both, HbA1c dropped by an average of 2.6% (from 9.5%) and the level of triglycerides fell by a median of 374 mg/dL (from 500 mg/dL at baseline), he reported at the American Association of Clinical Endocrinologists meeting here.

Patients who have either inherited or acquired lipodystrophy, which is characterized by a loss of adipose tissue and leptin deficiency, often have severe metabolic abnormalities accompanying an accumulation of excess fat in the blood, liver, and muscle.

These patients -- of whom there are only about 1,000 in the U.S. -- receive traditional medications for these problems, usually very high doses of insulin, according to Yehuda Handelsman, MD, a private practice endocrinologist in Tarzana, Calif., and AACE president, who was not involved in the study.

But the magnitude of the drop in HbA1c in the current study with metreleptin is not seen with standard drugs, and most patients remain uncontrolled, Handelsman said in an interview.

"[Metreleptin is] very promising," he said. "For these people, it's a replacement hormone they do not have. And this is a life-changing experience."

Weyer reported data from an open-label NIH study that has been ongoing since 1999. Previous analyses have been reported, but never in a cohort as large as 55 patients, according to Weyer.

To enroll in the study, patients had to have low leptin levels and at least one of the following -- diabetes, a fasting insulin level greater than 30 µU/mL, or a fasting triglyceride level greater than 200 mg/dL. Consistent with the pattern for the disease, most of the patients (80%) were female.

Metreleptin was administered subcutaneously once or twice a day at an average daily dose of 2.75 mg for males and 5.55 mg for females.

The 55 patients in the current analysis received treatment ranging from three months to nine years (median 2.5 years), with 30% treated for more than six years.

Overall at baseline, the average HbA1c was 8.5%, fasting plasma glucose level was 184.4 mg/dL, and triglyceride level was 1,185 mg/dL.

At three years in the overall cohort, the mean reduction in HbA1c was 2.1%, in fasting glucose 55 mg/dL, and in triglycerides 730 mg/dL. The median reduction in triglycerides was 253 mg/dL (from a median of 400 mg/dL at baseline).

Seventeen of the patients had a treatment-emergent adverse event judged to be related to metreleptin, including fatigue, hypoglycemia, alopecia, and weight loss, which mostly occurred within the first year of treatment.

Two patients developed T-cell lymphoma -- both had acquired lipodystrophy, immunodeficiency, and abnormal bone marrow biopsies at baseline.

Other adverse events were generally consistent with the known comorbidities of lipodystrophy -- pancreatitis, proteinuria, and autoimmune hepatitis.

Two patients had injection site reactions.

Weyer said that Amylin is in the process of submitting data to the FDA to get metreleptin approved, and expects the company to complete the submission by the end of the year. Because the agent is for a rare disease, the approval is done with a rolling submission.

Weyer is an employee of Amylin Pharmaceuticals, which is developing metreleptin.

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